This invention relates to new aryloxy indole derivatives as pharmaceuticals which are useful for the treatment in mammals of diseases affected by disorders of the serotonin-affected neurological systems, such as depression, anxiety, panic disorder, obsessive-compulsive disorder, sleep disorders, sexual dysfunction, alcohol and drug, addiction, Alzheimer""s disease, Parkinson""s disease, obesity and migraine, as well as methods of enhancing cognition.
EP 0714894 A1 discloses the preparation of compounds of formula II as new 5-HT1f agonist for the treatment of migraine headaches. EP 429341 A2 claims compounds of formula III as having serotonin transporter activity. A recent publication by Malleron et al. was also reported based around formula I [J. Med. Chem. 36, 1194 (1993)]. EP 722941 A2 discloses compounds having effects on serotonin-related systems of formula IV. 
Pharmaceuticals which enhance serotonergic neurotransmission are of useful benefit for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin (5-HT) reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism per se cannot account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of 5-HT neuron, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients. Recent studies by Artigas et al. (Trends Neurosci., 1996, 19, 378-383) suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concomitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
The compounds of this invention are aryloxy piperidinyl indoles represented by Formula I: 
R1 and R2 may each be hydrogen or an alkyl of from 1 to 6 carbon atoms or an alkoxy group of from 1 to 6 carbon atoms; or
R1 and R2 may be concatenated to comprise another ring system wherein the ring contains a total of 5-7 ring members;
X is selected from hydrogen, halogen, cyano, C1-C6 alkoxy;
Z is (CH2)n or carbonyl;
n is 0, 1 or 2;
the dashed line indicates an optional double bond; or a pharmaceutically acceptable salt thereof.
Ring systems formed by the concatenation of R1 and R2 are understood to contain the carbon or oxygen atoms of the R1 and R2 groups and can being saturated or unsaturated, including fused alkyl, pyran, or dioxan ring systems. With the phenyl ring to which they are bound, the concatenated rings can form the moieties: 
One group of compounds of this invention comprises compounds of the formula: 
wherein X is selected from H, halogen, cyano, C1-C6 alkoxy; Z is (CH2)n or carbonyl;
and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
Another group of compounds of this invention comprises those of the formula: 
wherein X is H, halogen, cyano, C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof.
A further group of compounds of this invention, and pharmaceutically acceptable salts thereof, are represented by the formula: 
wherein X and Z are as defined above.
The compounds of this Formula I also may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
The compounds of Formula I are generally prepared by the overall sequence indicated in Scheme 1 and 2 as follows: 
The following examples for preparation of intermediates and invention compounds are included for illustrative purposes and are not to be construed as limiting to this disclosure in any way. Those skilled in the art of organic synthesis may be aware of still other synthetic routes to the invention compounds. The reagents and intermediates used herein are either commercially available or prepared according to standard literature procedures.
To a solution of 2-methoxyphenol (14.4 g, 116 mmol) in 2-butanone (200 mL) was added bromochloroethane (69.0 g, 480 mmol) followed by the addition of potassium carbonate (40.0 g, 280 mmol). The reaction mixture was mechanically stirred and heated to reflux for 24 h, then cooled to room temperature. The solids were filtered off and the solvent was removed under vacuum. The residue was dissolved in diethyl ether and washed with 10% of NaOH, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel column chromatography (25% EtOAc/hexane) afforded 7.55 g (35%) of a solid: mp 36-38xc2x0C. (Lit.2 41-43xc2x0 C,); 1H NMR (DMSO, 400 MHz), 3.75 (s, 3H), 3.91 (dd, 2H), 4.20 (dd, 2H), 6.86-6.99 (m, 4H); MS (EI) m/z 186 (M+).
Replacing 2-methoxyphenol with commercially available 5-hydroxyindane and using the above procedure afforded the title compound in 43% yield as a white solid: mp 45-46xc2x0 C.
Elemental Analysis Calcd for C11H13OCl Theory: C, 67.18; H, 6.66 Found: C, 67.03; H, 6.57
Pyrogallol (5 g, 0.04 mmol) was dissolved in 2-butanone (600 mL) to which potassium carbonate (1.82 g, 0.013 mol) was added. The mixture was stirred at reflux while 1,2-dibromoethane (2.48 g, 1.14 mL, 0.013 mol) was slowly added drop wise. The reaction was allowed to stir overnight and then cooled to room temperature. The mixture was poured into water (100 mL) and extracted with methylene chloride (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed under vacuum. Chromatography (5% methanol-methylene chloride) afforded 2.74 g (45%) of a clear oil.
To solution of 5-hydroxy benzodioxan (1 g, 6.5 mmol) and 2-chloroethanol (0.79 g, 9.9 mmol), triphenylphosphine (2.6 g, 9.9 mmol) in THF (50 mL) was slowly added diisopropylazidodicarbimide (DIAD) (2.0 g, 9.8 mmol). After 2 h, another 1.5 eq of triphenylphosphine, DIAD, and 2-chloroethanol was added and the reaction stirred for another 2 h. The reaction mixture was poured into water (100 mL), and extracted with methylene chloride (100 mL). The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. Chromatography (ethyl acetate-hexane: 1:4) afforded 1.7 g (76%) or a white solid: mp 70.5-72.5xc2x0 C.
Elemental Analysis for C10H11ClO3 Theory: C, 55.96; H, 5.17 Found: C, 55.57; H, 5.20
To a stirred solution of 5-fluoroindole (3.10 g, 23.0 mmol) in methanol (10.0 mL) was added 4-pyridinecarboxaldehyde (2.20 mL, 23.0 mmol), followed by addition of NaOH (2.5 mL, 50%) at 0xc2x0 C. After stirring for 1 h at 0xc2x0 C., the reaction Mixture was warmed to room temperature and stirred for 3 h, followed by the addition of water (10.0 mL). The precipitate was collected by filtration and dried under vacuum to afford 5.2 g (93%) of a light yellow solid: mp 171-173xc2x0 C.; 1H NMR (DMSO, 400 MHz), 5.85 (d, 1H), 5.93 (d, 1H), 6.86-7.34 (m, 4H), 7.43 (dd, 2H), 8.48 (dd, 2H), 11.09 (br s, 1H); MS (EI) m/z 242 (M+); HRMS calcd for C14H12FN2O [M+H] 243.09337, found 243.09576.
To a suspension of (5-fluoro-1H-indol-3-yl)-pyridin-4-yl-methanol (0.799 g, 3.3 mmol) in methylene chloride (13 mL) was added triethylsilane (0.60 mL, 3.7 mmol) followed by trifluoroacetic acid (2.85 mL, 37 mmol) at room temperature. After addition of trifluoroacetic acid, a clear black solution was obtained. The reaction mixture was stirred overnight and the solvent and excess trifluoroacetic acid was removed on a rotary evaporator. To the residue was added saturated Na2CO3 to adjust the pH greater than 9. The aqueous layer was extracted with methylene chloride and the combined organic extracts was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methylene chloride to methylene chloride/ethyl acetate to ethyl acetate, 100% to 50% to 100%) to give 0.56 g (75%) of a solid: mp 141-142xc2x0 C. [(mp 149xc2x0 C.; previously reported in J. Med. Chem. 36, 1194 (1993)].
This compound was prepared in 88% yield following the reported procedure (Malleron et al., J. Med. Chem. 1993, 36,1194).
A solution of 6-fluoroindole (2 g, 15 mmol) and 4-piperidone (3 g, 19.6 mmol) in 2 N solution of KOH in MeOH (60 mL) was stirred at reflux for 72 h. The mixture was concentrated to xc2xc volume, diluted with H20 and filtered affording 2.5 g (77%) as a pale yellow solid: mp 202-204xc2x0 C.; MS (APCI) m/z 217 [M+H]+.
Replacing 6-fluoroindole with indole in the above procedure afforded the title compound % as a pale yellow solid.
Replacing 6-fluoroindole with 5-fluoroindole in the above procedure afforded the title compound % as a yellow solid.